ES2857549T3 - Opioid receptor ligands and methods of using and obtaining them - Google Patents

Abstract

A pharmaceutical composition comprising a compound having a formula of ** (See formula) ** or ** (See formula) ** or a pharmaceutically acceptable salt thereof, for use in the treatment of pain by parenteral administration.

Description

DESCRIPTION

Opioid receptor ligands and methods of using and obtaining them

Countryside

This application relates to compounds that act as ligands for opioid receptors. Such compounds can provide therapeutic benefits in the treatment of pain.

Background

Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically different types of opioid receptors have been described: 5, k, and g. Furthermore, each type is believed to have subtypes. All three types of opioid receptors appear to share the same functional mechanisms at the cellular level. For example, activation of opioid receptors causes inhibition of adenylate cyclase and recruits p-arrestin.

When therapeutic doses of morphine are given to patients in pain, patients report that the pain is less severe, less uncomfortable, or disappears completely. In addition to experiencing relief from grief, some patients experience euphoria. However, when morphine is given in a dose selected for pain relief to a pain-free individual, the experience is not always pleasant; nausea is common and vomiting may also occur. It can cause drowsiness, inability to concentrate, difficulty in mental activity, apathy, decreased physical activity, reduced visual acuity, and lethargy. US 2009/024756 A1 describes compounds having affinity for the g-opioid receptor and ORL1 receptor, methods for their production, drugs containing these compounds, and the use of these compounds for the treatment of pain and other conditions.

There is a constant need for new OR modulators for use as pain relievers. There is a further need for OR agonists as analgesics that have reduced side effects. There is an additional need for OR agonists as analgesics that have reduced side effects for the treatment of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions, urological and reproductive conditions, drugs for drug and alcohol use, agents for the treatment of gastritis and diarrhea, cardiovascular agents and / or agents for the treatment of respiratory diseases and coughs.

Compendium

This application describes a pharmaceutical composition comprising a compound having a formula of

or a pharmaceutically acceptable salt thereof, for use in the treatment of pain by parenteral administration.

This application also describes pharmaceutical compositions comprising one or more compounds as described in this application and a pharmaceutically acceptable carrier. Of course, the compounds described herein can be used in any form, such as a solid or solution (eg, aqueous solution) as further described below. The compounds described herein, for example, can be made and used in a lyophilized form alone or with suitable additives.

Detailed description

This application describes pharmaceutical compositions comprising compounds, OR ligands, with a unique profile. The compounds described herein act as agonists or antagonists of opioid receptor (OR) mediated signal transduction. Ligands for these receptors can be used to treat pathologies associated with ORs, including pain and pain-related disorders.

The following compounds and others described herein have antagonistic activity for OR-mediated signal transduction:

[(4-chlorophenyl) methyl] ({2- [4- (4-methoxyphenyl) -2,2-dimethyloxan-4-yl] ethyl}) amine, [(3,4-dimethoxyphenyl) methyl] [2- ( 2,2-dimethyl-4-phenyloxan-4-yl) ethyl] amine, 2 - [({2- [2-ethyl-2-methyl-4- (4-methylphenyl) oxan-4-yl] ethyl} amino ) methyl] phenol [2- (2,2-dimethyl-4-phenyloxan-4-yl) ethyl] [(2-fluorophenyl) methyl] amine, 4 - [({2- [4- (2-methoxyphenyl) - 2,2-dimethyloxan-4-yl] ethyl} amino) methyl] -N, N-dimethylaniline, 2 - [({2- [2-ethyl-4- (4-fluorophenyl) -2-methyloxan-4-yl ] ethyl} amino) methyl] phenol [(3-methoxythiophen-2-yl) methyl] ({2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethyl}) amine.

Compositions are provided for use in treating pain by parenteral administration.

Thus, the application provides compositions for use in generating agonist activity in OR-mediated signal transduction in a subject in need thereof.

Various atoms in the compositions described herein may be isotopes that occur at a lower frequency. Hydrogen can be replaced at any position in the compositions described herein by deuterium. Optionally, hydrogen can also be replaced by tritium. Carbon (12C) can be replaced at any position in the compositions described herein by 13C or 14C. Nitrogen (14N) can be replaced by 15N. Oxygen (16O) can be replaced at any position in the compositions described herein by 17O or 18O. Sulfur (32S) can be replaced at any position in the compositions described herein by 33S, 34S or 36S. Chlorine (35Cl) can be replaced at any position in the compositions described herein by 37Cl. Bromine (79Br) can be replaced at any position in the compositions described herein by 81Br.

The selected compositions described herein are opioid receptor (OR) agonists and antagonists. The ability of the compositions to stimulate OR-mediated signaling can be measured using any assay known in the art for detecting OR-mediated signaling or OR activity or the absence of such signaling / activity. "OR activity" refers to the ability of an OR to transduce a signal. Said activity can be measured, for example, in a heterologous cell, by coupling an OR (or a chimeric OR) to a downstream effector such as adenylate cyclase.

A "natural ligand-induced activity" as used herein refers to an activation of the OR by a natural ligand of the OR. Activity can be assessed using any number of endpoints to measure the activity of the OR.

Generally, tests to evaluate compounds that modulate signal transduction as measured by OR include the determination of any parameter that is indirectly or directly under the influence of an OR, for example, a functional, physical or chemical effect.

Samples or assays comprising ORs that are treated with a possible activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition. Control samples (not treated with inhibitors) are assigned a relative OR activity value of 100%. The inhibition of an OR is achieved when the value of the activity of the OR with respect to the control is approximately 80%, 50% or 25%. The activation of an OR is achieved when the value of the activity of the OR with respect to the control (not treated with activators) is 110%, 150%, 200-500% (that is, two to five times higher than the control ) or 1000-3000% or higher.

The effects of compounds upon OR function can be measured by examining any of the parameters described above. Any suitable physiological change that affects OR activity can be used to assess the influence of a compound on ORs and natural ligand mediated OR activity. When functional consequences are determined using intact cells or animals, a variety of effects such as changes in intracellular second messengers such as cAMP can also be measured.

Modulators of OR activity are evaluated using OR polypeptides as described above, whether they are recombinant or natural. The protein can be isolated, expressed in a cell, expressed on a cell-derived membrane, expressed in tissue or in an animal. For example, neuronal cells, immune system cells, transformed cells, or membranes can be used to evaluate the GPCR polypeptides described above. Modulation is evaluated using one of the in vitro or in vivo assays described herein. Signal transduction can also be examined in vitro with soluble or solid state reactions, using a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain or a heterologous extracellular domain covalently linked to the transmembrane. I cytoplasmic domain of a receptor. Furthermore, the ligand-bound domains of the protein of interest can be used in vitro in soluble or solid state reactions to assess ligand binding.

Binding of the ligand to an OR, domain, or chimeric protein can be evaluated in various formats. The binding can be done in solution, on a bilayer membrane, bound to a solid phase, on a lipid monolayer or on vesicles. Typically, in an assay described herein, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator. Alternatively, the binding of the candidate modulator can be measured in the presence of the natural ligand. Competitive assays are often used that measure the ability of a compound to compete with the binding of the natural ligand to the receptor. Binding can be evaluated by measuring, for example, changes in spectroscopic characteristics (eg, fluorescence, absorbance, refractory index), hydrodynamic changes (eg, shape), or changes in solubility or chromatographic properties.

Modulators can also be identified using assays involving recruitment of p-arrestin. Parrestin serves as a regulatory protein that is distributed throughout the cytoplasm in non-activated cells. Ligand binding to an appropriate OR is associated with redistribution of p-arrestin from the cytoplasm to the cell surface, where it is associated with the OR. Thus, receptor activation and the effect of candidate modulators on ligand-induced receptor activation can be assessed by monitoring the recruitment of p-arrestin to the cell surface. This is frequently done by transfecting a tagged p-arrestin fusion protein (eg, p-arrestin-green fluorescent protein (GFP)) into cells and monitoring its distribution using confocal microscopy (see, for example, Groarke et al., J. Biol. Chem. 274 (33): 23263-69 (1999)).

Another technology that can be used to evaluate OR-protein interactions in living cells involves bioluminescence resonance energy transfer (BRET). A detailed discussion regarding BRET can be found in Kroeger et al., J. Biol. Chem., 276 (16): 1273643 (2001).

Other assays may involve determining the activity of receptors that, when active by ligand binding, result in a change in the level of intracellular cyclic nucleotides, eg, cAMP, by activation or inhibition of downstream effectors such as adenylate cyclase. . Changes in intracellular cAMP can be measured using immunoassays. The method described in Offermanns & Simon, J. Biol. Chem. 270: 15175 15180 (1995) can be used to determine the level of cAMP. Likewise, the method described in Felley-Bosco et al., Am. J. Resp. Cel and Mol. Biol. 11: 159 164 (1994) can be used to determine the level of cGMP. Furthermore, an assay kit for measuring cAMP is described in US Patent No. 4,115,538.

Transcription levels can be measured to assess the effects of a test compound on ligand-induced signal transduction. A host cell containing the protein of interest is contacted with a test compound in the presence of the natural ligand for a time sufficient to effect any interaction and then the level of gene expression is measured. The amount of time to effect such interactions can be determined empirically, such as by following a time trajectory and measuring the level of transcription as a function of time. The amount of transcription can be measured using any known method that is suitable to those of skill in the art. For example, mRNA expression of the protein of interest can be detected using northern blot or its polypeptide products can be identified using immunoassays. Alternatively, transcription-based assays using reporter genes can be used as described in US Patent No. 5,436,128. Reporter genes can be, for example, chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, p-galactosidase, and alkaline phosphatase. Furthermore, the protein of interest can be used as an indirect reporter through binding to a second reporter such as green fluorescent protein (see, eg, Mistili & Spector, Nature Biotechnology 15: 961 964 (1997)).

The amount of transcription is then compared to the amount of transcription in the same cell in the absence of the test compound or it can be compared to the amount of transcription in a substantially identical cell lacking the protein of interest. A substantially identical cell can be derived from the same cells from which the recombinant cell was prepared but which has not been modified by the introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound has somehow altered the activity of the protein of interest.

Pharmaceutical compositions / formulations

Pharmaceutical compositions can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. The formulations may contain a buffer and / or a preservative. The compounds and their physiologically acceptable salts and solvates are formulated for administration parenterally (eg, intravenously, intraperitoneally, intravesically, or intrathecally) in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, the chosen route of administration and standard biological practice.

Pharmaceutical compositions can include effective amounts of one or more compounds described herein together with, for example, diluents, preservatives, solubilizers, emulsifiers, adjuvants, and / or other pharmaceutically acceptable carriers. Such compositions may include diluents of various buffer contents (for example, TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-glycylglycine, sodium phosphate or potassium (dibasic, tribasic), etc, or TRIS-HCl or acetate), pH and ionic strength; additives such as detergents and solubilizing agents (eg surfactants such as Pluronics, Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.), antioxidants (eg ascorbic acid, sodium metabisulfite ), preservatives (for example, thiomerosal, benzyl alcohol, parabens, etc,) and thickening substances (for example, sugars such as sucrose, lactose, mannitol, polymers such as polyvinylpyrrolidones or dextran, etc,); and / or incorporation of the material in particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc, or in liposomes. Hyaluronic acid can also be used. Such compositions can be used to influence the physical state, stability, in vivo release rate, and in vivo clearance rate of a compound described herein. See, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.

18042) pages 1435-1712. The compositions can be prepared, for example, in liquid form or they can be a dry powder, such as in lyophilized form. Particular methods for administering such compositions are described infra.

When a buffer is to be included in the formulations described herein, the buffer can be selected from sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphate sodium and tris (hydroxymethyl) -aminomethane or mixtures thereof. The buffer solution can also be glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium phosphate or mixtures thereof.

When a pharmaceutically acceptable preservative is to be included in a formulation of one of the compounds described herein, the preservative can be selected from phenol, m-cresol, methyl p-hydroxybenzoate, propyl phhydroxybenzoate, 2-phenoxyethanol, p-hydroxybenzoate butyl, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal or mixtures thereof. The preservative can also be phenol or m-cresol.

The preservative is present in a concentration of about 0.1 mg / ml to about 50 mg / ml, in a concentration of about 0.1 mg / ml to about 25 mg / ml, or in a concentration of about 0.1 mg / ml. ml to about 10 mg / ml.

The use of a preservative in pharmaceutical compositions is well known to those of skill in the art. For the convenience of the reader, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

The formulation may further comprise a chelating agent wherein the chelating agent can be selected from salts of ethylenediaminetetraacetic acid (EDTA), citric acid and aspartic acid and mixtures thereof.

The chelating agent can be present in a concentration of 0.1 mg / ml to 5 mg / ml, 0.1 mg / ml to 2 mg / ml, or 2 mg / ml to 5 mg / ml.

The use of a chelating agent in pharmaceutical compositions is well known to one of ordinary skill in the art. For the convenience of the reader, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

The formulation of the compounds described herein may further comprise a stabilizer that is selected from high molecular weight polymers and low molecular weight compounds wherein said stabilizers include, but are not limited to, polyethylene glycol (eg, PEG 3350). , polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (for example sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan and threonine or any mixture thereof. The stabilizer can also be L-histidine, imidazole or arginine.

The high molecular weight polymer may be present in a concentration of 0.1 mg / ml to 50 mg / m, 0.1 mg / ml to 5 mg / ml, 5 mg / ml to 10 mg / ml, of 10 mg / ml to 20 mg / ml, 20 mg / ml to 30 mg / ml, or 30 mg / ml to 50 mg / ml.

The low molecular weight compound may be present in a concentration of 0.1 mg / ml to 50 mg / ml, 0.1 mg / ml to 5 mg / ml, 5 mg / ml to 10 mg / ml, of 10 mg / ml to 20 mg / ml, 20 mg / ml to 30 mg / ml, or 30 mg / ml to 50 mg / ml.

The use of a stabilizer in pharmaceutical compositions is well known to those of skill in the art. For the convenience of the reader, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

The formulation of the compounds described herein may further include a surfactant. In some embodiments, the surfactant may be selected from a detergent, ethoxylated castor oil, polyglycolized glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, derived from polyoxyethylene such as alkylated and alkoxylated derivatives (tweens, for example Tween-20 or Tween-80), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, cephalins, phosphatidyl serine), glyceroglycolipids (galactopyranoside), sphingofospholipids (sphingomyelin) and sphingoglycolipids (ceramides, gangliosides), DScyl S (docusate sodium docusate or sodium docusate sulfate, or sodium docussulfate sodium docusate sodium), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts of themselves and conjugates of glycine or taurine, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimethyl-3-ammonium-1-propanesulfonate, anionic monovalent surfactants (alkyl -aryl sulfonates), palmitoyl lysophosphatidyl-L-serine, lysophospholipids (for example 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxy (alkyl ester), derivatives (alkyl ether) of alkoxy of lysophosphatidyl and phosphatidylcholines, for example lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine and modifications of the polar head group, i.e. hills, ethanolamines, phosphatidic acid, serines, threonines, DODAC glycerol and el DOTMA, DCP, BISHOP positively charged, lysophosphatidylserine and lysophosphatidyl threonine, zwitterionic surfactants (e.g. N-alkyl-N, N-dimethylammonium-1-propanesulfonates, 3-cholamido-1-propyldimethylammonium-1-pro panesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, chicken egg lysolecithin), surfactants cationics (quaternary ammonium bases) (e.g. cetyl trimethylammonium bromide, cetylpyridinium chloride), nonionic surfactants, polyethylene oxide / polypropylene oxide block copolymers (Pluronics / Tetronics, Triton X-100, Dodecyl pD-glucopyranoside ) or polymeric surfactants (Tween-40, Tween-80, Brij-35), derivatives of fusidic acid - (for example sodium tauro-dihydrofusidate etc.), long chain fatty acids and salts thereof C6-C12 ( e.g. oleic acid and caprylic acid), acylcarnitines and derivatives, N ^a -acylated derivatives of lysine, arginine or histidine or acylated side chain derivatives of lysine or arginine, N ^a -acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, acylated derivative N ^to a tripeptide comprising any combination of a neutral amino acid and two charged amino acids , or the surfactant may be selected from the group imidazo line or mixtures thereof.

The use of a surfactant in pharmaceutical compositions is well known to one of ordinary skill in the art. For the convenience of the reader, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

Pharmaceutically acceptable sweeteners can be part of the formulation of the compounds described herein. Pharmaceutically acceptable sweeteners include at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside, or sucralose (4,1 ', 6'- trichloro-4,1 ', 6'-trideoxygalactosucrose), saccharin, sodium or calcium saccharin and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel and honey.

Strong sweeteners are conventionally used in low concentrations. For example, in the case of sodium saccharin, the concentration may be in the range of 0.04% to 0.1% (w / v) based on the total volume of the final formulation or is approximately 0.06% in low dosage formulations and approximately 0.08% in high dosage formulations. The bulk sweetener can be used effectively in larger amounts in the range of about 10% to about 35% or about 10% to 15% (w / v).

Formulations of the compounds described herein can be prepared by conventional techniques, for example as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995, wherein said industry standard techniques Pharmaceuticals involve dissolving and mixing the ingredients as appropriate to provide the desired end product.

The phrase "pharmaceutically acceptable" or "therapeutically acceptable" refers to molecular moieties and compositions that are physiologically tolerable and preferably do not typically produce an allergic or other similar inappropriate reaction, such as gastric upset, dizziness, and the like, when administered to a patient. human. As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or State government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia (eg, Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985)) for use in animals and more particularly in humans.

The administration of the compositions is carried out by parenteral administration.

For parenteral administration, the compositions described herein are administered by intravenous, subcutaneous, or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers. The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use.

For administration by injection, the composition (s) may be used in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives, as well as sufficient amounts of pharmaceutically acceptable salts or glucose to render isotonic solution. The pharmaceutical compositions of the compounds described herein can be formulated with a pharmaceutically acceptable carrier to provide sterile solutions or suspensions for injectable administration. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspensions in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride or the like. In addition, if desired, injectable pharmaceutical compositions may contain small amounts of non-toxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption-enhancing preparations (eg, liposomes) can be used. Pharmaceutically suitable carriers are described in "Remington's pharmaceutical Sciences" by E. W. Martin.

Furthermore, the compounds can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, compounds can be formulated with materials suitable polymeric or hydrophobic (eg as an emulsion in an acceptable oil) or ion exchange resins or as moderately soluble derivatives, eg as a moderately soluble salt.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The package may comprise, for example, foil or plastic, such as a blister pack. The package or dispensing device may include instructions for administration.

The compounds described herein also include derivatives called prodrugs, which can be prepared by modifying functional groups present in the compounds so that the modifications are cleaved, either on routine manipulation or in vivo, to the parent compounds. Examples of prodrugs include compounds of the invention as described herein that contain one or more molecular moieties attached to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound and that when administered to a patient, are cleaved in vivo to form the free hydroxyl, amino, sulfhydryl or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. The preparation and use of prodrugs are described in T. Higuchi et al., "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

Dosages

The compositions disclosed herein can be administered to a patient at a therapeutically effective dose to prevent, treat, or control one or more diseases and disorders mediated, in whole or in part, by an OR-ligand interaction. Pharmaceutical compositions comprising one or more of the compounds described herein can be administered to a patient in an amount sufficient to elicit an effective protective or therapeutic response in the patient. An amount adequate to accomplish this is defined as a "therapeutically effective dose." The dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the area to be treated. The size of the dose will also be determined by the existence, nature and extent of any adverse effects accompanying the administration of a particular compound or vector in a particular subject.

The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the lethal dose for 50% of the population) and the ED50 (the therapeutically effective dose in the 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the LD50 / ED50 ratio. In some embodiments, compounds that exhibit high therapeutic indices are used. Although compounds that exhibit toxic side effects can be used, care must be taken in designing a delivery system that targets such compounds to the affected tissue site to minimize potential damage to normal cells and thus reduce side effects.

Data obtained from cell culture assays and animal studies can be used to formulate a range of dosage for use in humans. In some embodiments, the dosage of such compounds lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending on the dosage form employed and the route of administration. For any compound described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a concentration range in circulating plasma that includes the IC50 (the concentration of test compounds that achieves a mean-maximum inhibition of symptoms), as determined in cell culture. Such information can be used to more accurately determine the useful dose in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC). In general, the equivalent dose of a modulator is from about 1 ng / kg to 10 mg / kg for a typical subject.

The amount and frequency of administration of the compounds described herein and / or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the treating physician considering factors such as age, condition and size of the patient, as well as the severity. symptoms treated. A physician or veterinarian skilled in the art will be able to easily determine and prescribe the effective amount of the drug required to prevent, counteract, or halt the progression of the condition. In general it is contemplated that an effective amount would be 0.001 mg / kg to 10 mg / kg of body weight and in particular 0.01 mg / kg to 1 mg / kg of body weight. It may be appropriate to administer the necessary dose as two, three, four or more subdoses at appropriate intervals throughout the day. Said subdoses can be formulated as unit dosage forms, for example, containing 0.01 to 500 mg and in particular 0.1 to 200 mg of active ingredient per unit dosage form.

In some embodiments, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate amounts of the active component, eg, an effective amount to achieve the desired purpose. The amount of active compound in a unit dose of preparation can be varied or adjusted from about 0.01 mg to about 1000 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 500 mg, or from about 0.01 mg to approximately 250 mg, depending on the application particular. The actual dosage employed may vary depending on the requirements of the patient and the severity of the condition being treated. Determination of the appropriate dosage regimen for a particular situation is within the art. For convenience, the total dosage can be divided and administered in portions throughout the day as required.

In some embodiments, one or more compounds described herein are administered with another compound. Administration can be sequential or simultaneous. The combination can be in the same dosage form or administered as a separate dose. In some embodiments, the other compound is another pain reliever. In some embodiments, the other compound is a non-opioid analgesic. Examples of useful non-opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, oxoprofen, wallofen, carofzprofen, piroprofen, carofprofen. trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, buclofenic acid, indomethacin, sulindac, tolmetin, zomepirac, thiopinac, zidomethacin, acemethacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenmic acid, diphenamic acid, meclofenamic acid, diphenamic acid , flufenisal, piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof and mixtures thereof. Other suitable non-opioid analgesics include the following, but are not limited to, chemical classes of analgesics, antipyretics, non-steroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid , sulfasalazine and olsalazine; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicam (piroxicam, tenoxicam) and pyrazolidinediones (phenylbutazone, oxyphentartazone); and alkanones, including nabumetone. For a more detailed description of NSAIDs, see Paul A. Insel, Analgesic-Antipiretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W Ruddon eds., 9th ed 1996); and Glen R. Hanson, Analgesic, Antipiretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196 1221 (A. R. Gennaro ed. 19th ed. 1995).

The compounds described herein can also be administered with Cox-II inhibitors. Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in US Patent No. 6,136,839. Examples of Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.

The compounds described herein can also be administered with antimigraine agents. Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocriptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazomer, ketansyleroline, lysuride, methoxyleroline, lisuride naratriptan, oxetorone, pizotiline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.

The compounds described herein can also be administered with anti-constipation agents. Examples of anti-constipation agents include, but are not limited to, laxatives or stool softeners. Examples of anti-constipation agents include, but are not limited to, docusate, poloxamer 188, psillium, methylcellulose, carboxymethylcellulose, polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesium hydroxide, magnesium sulfate, dibasic sodium phosphate, phosphate of monobasic sodium, sodium bisphosphate, or any combination thereof.

Medical use

The compositions described herein may be useful for the treatment of pain or pain associated with disorders.

Compositions useful for treating pain are provided. In some embodiments, the pain can be postoperative pain. In some embodiments, the pain is caused by cancer. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is caused by trauma such as, but not limited to, blunt trauma. In some embodiments, the pain is caused by inflammation.

The compositions are administered parenterally (eg, intravenously, intraperitoneally, intravesically, or intrathecally) in a vehicle comprising one or more pharmaceutically acceptable carriers, the ratio of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard practice.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While methods and materials similar or equivalent to those described herein may be used in the practice or testing of the compositions and compounds described in the present invention, suitable methods and materials are described below. Furthermore, the materials, methods, and examples are merely illustrative and are not intended to be limiting. Other features and Advantages of the compositions and compounds described herein will be apparent from the following detailed description and embodiments.

The general chemical terms used herein have their common meanings. For example, the term "alkyl" refers to a branched or unbranched saturated hydrocarbon group. The term "n-alkyl" refers to an unbranched alkyl group. The term "Cx-Cy alkyl" refers to an alkyl group having from x to y carbon atoms, inclusive, in the branched or unbranched hydrocarbon group. Illustratively, but not exclusively, the term "C ¹ -C ⁴ alkyl" refers to a straight or branched chain hydrocarbon moiety having 1 to 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl and tere-butyl. The term "C ¹ -C ⁴ nalkyl" refers to straight chain hydrocarbon moieties having 1 to 4 carbon atoms including methyl, ethyl, n-propyl, and n-butyl. X in Cx-Cy can be from 1 to 10 and y is from 2 to 20. The term "C ³ -C ⁶ cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "C ³ -C ⁷ cycloalkyl" also includes cycloheptyl. Cycloalkylalkyl refers to cycloalkyl moieties linked through an alkyl linking chain, such as, but not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, and cyclohexylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl. Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted, but not limited to, as specified herein. In some embodiments, the alkyl is a C ¹ -C ³ , C ¹ -C ⁴ , C ¹ -C ⁶ , C ⁴ -C ^6, or C ¹ -C10 alkyl.

The terms "alkoxy", "phenyloxy", "benzoxy" and "pyrimidinyloxy" refer to an alkyl group, phenyl group, benzyl group or pyrimidinyl group, respectively, that is linked through an oxygen atom. Each of these groups can be optionally substituted.

The terms "alkylthio", "phenylthio" and "benzylthio" refer to an alkyl group, phenyl group, or benzyl group, respectively, that is linked through a sulfur atom. Each of these groups can be optionally substituted.

The term "C ¹ -C ⁴ acyl" refers to a formyl group or a C ¹ -C ³ alkyl group linked through a carbonyl moiety. The term "C ¹ -C ⁴ alkoxycarbonyl" refers to a C ¹ -C ⁴ alkoxy group linked through a carbonyl moiety.

The term "halo" refers to fluoro, chloro, bromo, or iodo. In some embodiments, the halo groups are fluoro, chloro, and bromo. In some embodiments, the halo groups are fluoro and chloro.

As used herein, "carbocycle" or "carbocyclic ring" is intended to mean, unless otherwise indicated, any monocyclic, bicyclic, or tricyclic ring of 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 stable members, any of which can be saturated, unsaturated (including partially and fully unsaturated) or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0] bicyclooctane, [4.3.0] bicyclooctane, [4.3.0] bicyclooctane, [4.3.0] bicyclooctane , [4.4.0] bicyclodecane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (eg, [2.2.2] bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In some embodiments, the bridges are one or two carbon atoms. Notably, a bridge always converts a monocyclic ring to a tricyclic ring. When a ring is bridged, the indicated substituents for the ring may also be present on the bridge. Also included are fused (eg, naphthyl and tetrahydronaphthyl) and spiro rings.

The term "heterocycle" is taken to mean a 5- or 6-membered saturated or unsaturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, said ring being optionally benzofused. Exemplary heterocycles include furanyl, thiophenyl (thienyl), pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, pyridinyl, and the like. Benzofused heterocyclic rings include isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl, benzofuranyl, benzothiophenyl, indolyl and the like, which may be optionally substituted, which also includes, of course, optionally substituted on the benzo ring when the heterocycle is benzofused.

The term "cyclo" group is taken to mean a carbocyl ring, a carbocycle, or a heterocarbocyl.

As used herein, the phrase a "formula cycle" refers to a ring that can be formed with the referred variable. For example, in the structure

where A can be a ring of the formula C (CH ² ) n, where n = 2-5, means that A is a carbon and forms a ring with itself with 2-5 CH ² groups, which could also be represented structurally like

The variable "A" is not limited to carbon and may be another atom, such as, but not limited to, a heteroatom, but the context in which the variable is used will indicate the type of atom that "A" may be. This is only a non-exhaustive example. In addition, the ring that is formed with "A" can also be substituted. Exemplary substituents are described herein.

In some embodiments, heterocycles include, but are not limited to, pyridinyl, indolyl, furanyl, benzofuranyl, thiophenyl, benzodioxolyl, and thiazolidinyl, which may be optionally substituted.

As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable 5, 6, 7, 8, 9, 10, 11 or 12 membered monocyclic or bicyclic aromatic ring consisting of carbon atoms and one or more heteroatoms, eg, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, which are independently selected from nitrogen, oxygen and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings must be aromatic (eg, 2,3-dihydroindole), although both can be (eg quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom may or may not be substituted (ie, N or NR where R is H or another substituent, as defined). Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S (O) p, where p = 1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, bencisoxazolyl, benzisothiazolinyl, benzimidazolyl, caromannazolyl, 4-caromanazolyl, caromannazolyl, caromanazolyl, 4-caromanazolyl, crromanazolyl, caromanazolyl, 4 cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-¿>] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolnyl, indolinyl, indolizinyl, indolnyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxat hinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyrrolidinyl, pyridinyl, pyrrolidinyl, pyrrolidimidazol, pyridinyl, pyridinyl, pyridinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

"Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio" means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio group, respectively, substituted one or more times independently with a substituent selected from the group consisting of halo, hydroxy, and C ^{1 -alkoxy.} C ³ . Illustrative, but not limited to, examples include trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl, 3-hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio, 3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like. In some embodiments, the substitutions include substitution 1-5 times with halo, each independently selected or substitution 1-3 times with halo and 1-2 times independently with a group selected from hydroxy and C ¹ -C ³ alkoxy or 1-3 fold substitution independently with a group selected from hydroxy and C ¹ -C ³ alkoxy, provided that no more than one hydroxy and / or alkoxy substituent can be attached through the same carbon.

The terms "substituted phenyl" and "substituted heterocycle" mean that the cyclic moiety is in any case substituted. They can be independently substituted with one or more substituents. They can be independently substituted with 1,2, 3, 4, 5, 1-3, 1-4, or 1-5 substituents. The substitution can independently be halo, alkyl, such as, non-exhaustively, C ¹ -C ⁴ alkyl, alkoxy, such as non-exhaustive, C ¹ -C ⁴ alkoxy, and alkylthio, such as non-exhaustive , C ¹ -C ⁴ alkylthio, wherein each alkyl, alkoxy and alkylthio substituent may be further independently substituted by C ¹ -C ² alkoxy or by one to five halo groups; or substituted by a substituent selected from the group consisting of phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy moiety may be further substituted by one to two substituents selected from the group consisting of halo, C ¹ -C ² alkyl and C ¹ -C ² alkoxy; or substituted by a substituent selected from the group consisting of C ¹ -C ⁴ acyl and C ¹ -C ⁴ alkoxycarbonyl and additionally substituted with zero to a substituent selected from the group consisting of halo, C ¹ -C alkyl ⁴ , C ¹ -C ⁴ alkoxy and C ¹ -C ⁴ alkylthio. When a substituent is halo, in some embodiments, the halo groups are fluoro, chloro, and bromo. The halo can also be iodine.

DMF means N, N-dimethylformamide.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for use in contact with tissues. of humans and animals without excessive toxicity, irritation, allergic responses or other problems or complications, consistent with a reasonable risk / benefit ratio.

By "pharmaceutical formulation" it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (eg a compound described herein). One skilled in the art will understand that the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable and are therefore used in this way in this application.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, wherein the base compound is modified by obtaining acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the base compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycolylarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, mandelic, lactic, isethionic, lactic, lactic, maleic, isethionic, lactic, lactic napsilic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric and toluenesulfonic. The present disclosure includes pharmaceutically acceptable salts of any compound described herein.

Pharmaceutically acceptable salts can be synthesized from the base compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or a mixture of both; Nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile and the like are generally used. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).

Because prodrugs are known to improve numerous desirable qualities of pharmaceuticals (eg, solubility, bioavailability, manufacture, etc.), the compounds described herein can be provided in prodrug form and can be administered in this form for the purpose of disease treatment. "Prodrugs" are intended to include any covalently linked carrier that releases an active base drug of those described herein in vivo when said prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs include compounds described herein wherein a hydroxy, amino, or sulfhydryl group is attached to any group that cleaves to form a free hydroxy group, a free amino group, or a free sulfhydryl group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds described herein.

"Stable compound" and "stable structure" indicate a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

As used herein, "treating" or "treating" includes any effect, eg, diminish, reduce, modulate, or eliminate, that results in amelioration of the condition, disease, disorder, and so on. "Treating" or "treatment" of a disease state means treating a disease state in a mammal, particularly a human and includes: (a) inhibiting an existing disease state, that is, arresting its development or symptoms clinical; and / or (c) alleviating the disease state, ie, causing regression of the disease state.

As used herein, "preventing" means causing the clinical symptoms of the disease state to not develop, ie, inhibiting the onset of the disease, in a subject who may be exposed or predisposed to the disease state but not yet. have experienced or shown symptoms of the disease state.

As used herein, "mammal" refers to human and non-human patients.

As used herein, the term "therapeutically effective amount" refers to a compound, or a combination of compounds, described herein present in a receptor in an amount sufficient to elicit biological activity, eg, pain relief. . In some embodiments, the combination of compounds is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is more clearly demonstrated at suboptimal concentrations of the compounds. Synergy can occur in terms of lower cytotoxicity, greater decrease in pain, or some other beneficial effect of the combination compared to the individual components.

All percentages and ratios used herein, unless otherwise indicated, are by weight.

Throughout the description, where the compositions are described as having, include, or comprise specific components or where the processes are described as having, include, or comprise specific process steps, it is contemplated that the compositions described herein also consist essentially of or consist of, the mentioned components and that the processes described herein also essentially consist of or consist of, the mentioned processing steps. Also, it should be understood that the order of steps or order to perform certain actions are irrelevant as long as the process remains operable. Furthermore, two or more steps or actions can be carried out simultaneously.

All enantiomers, diastereomers, and mixtures thereof are included within the scope of the compounds described herein. In some embodiments a composition comprising the R enantiomer is free or substantially free of the S enantiomer. In some embodiments, a composition comprising the S enantiomer is free or substantially free of the R enantiomer. In some embodiments, a composition comprises an enantiomeric excess of at least or about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% of the R or S enantiomer.

As used throughout this disclosure, the singular forms "a" and "the" include references to the plural, unless the context clearly indicates otherwise. Thus, for example, a reference to "a composition" includes a plurality of such compositions, as well as a single composition, and a reference to "a therapeutic agent" is a reference to one or more therapeutic and / or pharmaceutical agents and equivalents. thereof known to those skilled in the art, etc. Thus, for example, a reference to "a host cell" includes a plurality of such host cells and a reference to "an antibody" is a reference to one or more antibodies and equivalents thereof known to those of skill in the art. , etc.

The compounds claimed in this invention can be prepared from the procedures described in the schemes below.

Schematics

The following representative schemes illustrate how the compounds described herein can be prepared. The specific solvents and reaction conditions mentioned are also illustrative and are not intended to be limiting. Compounds not described are commercially available or readily prepared by one of ordinary skill in the art using available starting materials.

Scheme 1: Synthesis of spirocyclic nitrile

Following a sequence that is described in Scheme 3, intermediate 4-4 can be converted to the opioid receptor ligands.

Scheme 5: Synthesis of other spirocyclic derived opioid ligands

n = 1-2

R and R-i are independent

R and R- | = phenyl, substituted emf, aryl, substituted ardo, pyridyl, substituted pmdyl, heteroaryl substituted heteroaryl, carbocycle, heterocycle and etc.

* only as a reference

Other schemes can also be used. For example, the following schemes can be used alone or in combination with other schemes to prepare the compounds described herein.

A process is provided for preparing a compound having the structure of IV-1

The process consists of putting in contact

OR

with V

under suitable conditions to form a compound having the structure of

The process can be carried out at room temperature. The process can be carried out in the presence of a borohydrate salt. The process can be carried out in the presence of sodium borohydrate. Solvents can also be used to facilitate preparation. The process can be modified to provide different alkyl groups such as, but not limited to, the schemes shown in Scheme 10.

Examples

The following examples are illustrative, but not limiting, of the methods and compositions described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in therapy, and which are obvious to those of skill in the art, are within the scope of the compounds and methods described herein.

Example 1:

intermediate 1: methyl 2-cyano-2- (oxan-4-ylidene) acetate

A 50 ml round bottom flask equipped with a Dean-Stark distillation setup and condenser was charged with tetrahydro-4H-pyran-4-one (4.61 ml, 50 mmol), methyl cyanoacetate (5.3 ml, 60 mmol), ammonium acetate (1 g, 13 mmol), acetic acid (0.57 ml, 10 mmol) and benzene (30 ml). The mixture was refluxed until no more water collected in the Dean-Stark (2 hours), cooled, benzene (30 ml) was added and the organic layer was washed with water (50 ml). The aqueous layer was extracted with CH ² Cl ² (3x50 ml). The combined organic phase was washed with sat. NaHCO3. (100 ml), brine (100 ml) dried (MgSO ⁴ ), filtered and concentrated. Purified by ^{normal phase SiO 2} chromatography (10 to 60% EtOAc / hexanes) to provide methyl 2-cyano-2- (oxan-4-ylidene) acetate as a colorless oil (observed: 6.30 g , 70%, m / z: 181.1 [MH] +).

intermediate 2: methyl 2-cyano-2- [4- (4-fluorophenyl) oxan-4-yl] acetate

A round bottom flask equipped with a condenser, addition funnel, and nitrogen inlet rubber septum was charged with a solution of p-fluorophenylmagnesium bromide (2.0 M in diethyl ether, 1.99 mL, 3.97 mmol ) and CuI (63 mg, 0.331 mmol) in 10 ml of dry diethyl ether (10 ml). Methyl 2-cyano-2- (oxan-4-ylidene) acetate (600 mg, 3.31 mmol) in diethyl ether (10 mL) was added dropwise over 30 min while cooling the reaction flask in a bath. of ice. The mixture was then stirred for 3h. The reaction mixture was poured into a 50 g ice / 1N HCl mixture (25 ml). The product was extracted with Et ² O (3x50 ml), washed with brine (50 ml), dried (Na2SO4) and concentrated. Purified by chromatography with ^{normal phase SiO 2} (7% to 60% EtOAc / hexanes) to provide methyl 2-cyano-2- [4- (4-fluorophenyl) oxan-4-yl] acetate as a white solid (found: 730 mg, 80%, m / z: 277.1 [M Na] +).

Intermediate 3: 2- [4- (4-fluorophenyl) oxan-4-yl] acetonitrile

To a previously dissolved solution of KOH (441 mg, 7.87 mmol) in ethylene glycol (20 ml) was added methyl 2-cyano-2- [4- (4-fluorophenyl) oxan-4-yl] acetate (1, 09 g, 3.93 mmol). The mixture was heated to 120 ° C for 3 h and then cooled. H ² O (50 ml) was added, the product was extracted with Et ² O (3x50 ml), washed with H ² O (50 ml), dried over Na2SO4, filtered and concentrated. Purified by ^{normal phase SiO 2} chromatography (5 to 40% EtOAc / hexanes) to provide 2- [4- (4-fluorophenyl) oxan-4-yl] acetonitrile as a colorless oil (observed: 450 mg, 78%, m / z: 219.1 [MH] +).

intermediate 4: 2- [4- (4-fluorophenyl) oxan-4-yl] ethan-1-amine

LAH (1.0 M in Et ² O, 4.1 mL, 4.11 mmol). After 2 h the reaction was quenched with 1 ml of H ² O ml, 0.1 ml of 15% NaOH and then 1 ml of H ² O. The reaction mixture was extracted with Et ² O (3x20 ml), dried over Na2SO4 and concentrated to provide 2- [4- (4-fluorophenyl) oxan-4-yl] ethan-1-amine as a yellow oil, which was used without further purification (found: 450 mg, 94%, m / z: 223.1 [MH] +).

Example 2: benzyl ({2- [4- (4-fluorophenyl) oxan-4-yl] ethyl}) amine (Compound 8)

To a solution of 2- [4- (4-fluorophenyl) oxan-4-yl] ethan-1-amine (250 mg, 1.12 mmol) in anhydrous CH ² Cl ² (5 ml) and Na2SO4 (159 mg, 1.12 mmol) at RT was added benzaldehyde (0.17 ml, 1.68 mmol). The reaction stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 5 ml of MeOH at 0 ° C and NaBH4 was added in one portion (51 mg, 1.34 mmol). The reaction was stirred at 0 [deg.] C. for 1 hr. The solution was then quenched with H ² O (10 ml), extracted with CH ² Cl ² (3x20 ml), washed with brine (10 ml) and dried over Na2SO4. It was purified by chromatography with ^{normal phase SiO 2} (0 to 10% MeOH / CH ² Cl ² ) to provide benzyl ({2- [4- (4-fluorophenyl) oxan-4-yl] ethyl}) amine as a colorless oil (observed: 200 mg, 60%, m / z: 314.2 [MH] +).

intermediate 5: 2,2-dimethyl-4- (4-methylphenyl) oxan-4-ol

N-BuLi (26.3 ml, 1.6 M in hexane, 42 mmol) was added dropwise to a solution of 4-bromo-toluene (7.70 g, 45 mmol) in THF (100 ml) at -78 ° C in N ² . The resulting mixture was stirred at -78 ° C for 30 min and a solution of tetrahydro-2,2-dimethyl-4H-pyran-4-one (3.84 g, 30 mmol) in THF (20 ml) was added. The resulting mixture was stirred at -78 ° C for another 20 min and quenched by adding MeOH (10 ml). The reaction was concentrated in vacuo and the resulting residue was diluted with EtOAc (500 mL) and washed with sat. NH4Cl. (250 ml), brine (250 ml), dried and concentrated to provide 2,2-dimethyl-4- (4-methylphenyl) oxan-4-ol as a white solid, which was used without further purification (5, 41 g, 82%).

1H NMR (400 MHz, CDCla) 57.36 - 7.26 (m, 2H), 7.11 (d, J = 8.0, 2H), 4.10 (td, J = 12.0, 2, 2.1H), 3.71 (ddd, J = 11.8, 5.0, 2.1, 1H), 2.28 (s, 3H), 2.11 (ddd, J = 13.7, 12 , 2, 5.0, 1H), 1.72 (dt, J = 14.2, 8.3, 2H), 1.58 (dq, J = 13.8, 2.2, 1H), 1, 44 (s, 3H), 1.38 (s, 1H), 1.14 (s, 3H).

intermediate 6: 2,2-dimethyl-4- (4-methylphenyl) -4- (prop-2-en-1-yl) oxane

Allyltrimethylsilane (4.34 ml, 27.2 mmol) was added to a solution of 2,2-dimethyl-4- (4-methylphenyl) oxan-4-ol (3.0 g, 13.6 mmol) in CH ^{Dry 2} Cl ² (100 mL) at 0 ° C then BF3-OEt2 (3.42 mL, 27.2 mmol). The resulting mixture was stirred at 0 ° C for 1 hr. The reaction was quenched with H ² O (10 mL) and diluted with CH ² Cl ² (10 mL) and washed with sat. NaHCO3. (20 ml), brine (20 ml), dried and concentrated. Purified ^{by normal phase SIO 2} chromatography (5 to 40% EtOAc / hexanes) to provide 2,2-dimethyl-4- (4-methylphenyl) -4- (prop-2-en-1-yl) oxane as a colorless oil, which was used crude (2.49 g, 75%).

Intermediate 7: 2- [2,2-dimethyl-4- (4-methylphenyl) oxan-4-yl] acetaldehyde

^{O 3} gas was passed through a solution of 2,2-dimethyl-4- (4-methylphenyl) -4- (prop-2-en-1-yl) oxane (1.21 g, 5 mmol) in CH ² Cl ² (50 ml) at -782C until the solution turned light blue (approximately 5 min). After an additional 5 minutes, the reaction mixture was purged with oxygen gas for 15 min before adding triphenylphosphine (2.62 g, 10 mmol). The reaction was stirred at RT for 4h and concentrated. Purified by ^{normal phase SiO 2} chromatography (10.-60% EtOAc / hexanes) to provide 2- [2,2-dimethyl-4- (4-methylphenyl) oxan-4-yl] acetaldehyde as a colorless oil (641 mg, 52%).

1H NMR (400 MHz, CDCla) 59.42-9.27 (m, 1H), 7.26 (dd, J = 9.9, 8.0, 2H), 7.20 (t, J = 8, 7.2H), 3.94-3.75 (m, 2H), 2.69 (dd, J = 14.6, 2.5, 1H), 2.51-2.38 (m, 2H), 2.35 (s, 3H), 2.26 (dd, J = 13.9, 2.3, 1H), 1.84 (ddd, J = 14.3, 11.0, 4.6, 1H) , 1.76 (d, J = 13.9, 1H), 1.23 (s, 3H), 0.73 (s, 3H).

Example 3: {2- [2,2-dimethyl-4- (4-methylphenyl) oxan-4-yl] ethyl}] (3-methylphenyl) methyl] amine (Compound 32)

A mixture of 2- [2,2-dimethyl-4- (4-methylphenyl) oxan-4-yl] acetaldehyde (61.6 mg, 0.25 mmol), 3-methylbenzylamine (63 gl, 0.5 mmol) and acetic acid (50 gl, 8.6 mmol) in CH ² CL (3 ml) was stirred at RT for 1h before adding sodium triacetoxyborohydride (106 mg, 0.50 mmol). The resulting mixture was stirred at RT for 18 h. The mixture was concentrated and dissolved in MeOH and purified by HPLC to provide {2- [2,2-dimethyl-4- (4-methylphenyl) oxan-4-yl] ethyl} [(3-methylphenyl) methyl] amine as a white solid (observed: 35 mg, 40%, m / z: 352.3 [MH] +).

Intermediate 8: 2-cyano-2 - [(9Z) -6-oxaspiro [4.5] decan-9-ylidene] methyl acetate

A 100 ml round bottom flask equipped with a Dean-Stark distillation setup and condenser was charged with 6-oxaspiro [4.5] decan-9-one (6 g, 39 mmol, which was prepared according to Hanschke, E. Chem. Ber. 1955, 88, 1053), methyl cyanoacetate (4.1 ml, 46.7 mmol), ammonium acetate (780 mg, 10.1 mmol), acetic acid (0.44 ml, 7.8 mmol) and benzene (40 ml). The mixture was refluxed until no more water collected in the Dean-Stark (2 hours), cooled, benzene (30 ml) was added and the organic product was washed with water (50 ml). The aqueous layer was extracted with CH ² CL (3x50 ml). The combined organic phase was washed with sat. NaHCO3. (100 ml), brine (100 ml) dried (MgSO4), filtered and concentrated. Purified by ^{normal phase SiO 2} chromatography (7% to 60% EtOAc / hexanes) to provide methyl 2-cyano-2 - [(9Z) -6-oxaspiro [4.5] decan-9-ylidene] acetate as a colorless oil (found: 8.93 g, 97.5%, m / z 235.1 [MH] +).

By the procedure for the preparation of Intermediate 8 substituting 2,2-diethyloxane-4-one for 6-oxaspiro [4.5] decan-9-one, 2-cyano-2 - [(4Z) -2,2-diethyloxane was prepared Methyl -4-ylidene] acetate (found: m / z 237.1 [MH] +).

By the procedure for the preparation of Intermediate 8 substituting 1-oxaspiro [5.5] undecan-4-one for 6-oxaspiro [4.5] decan-9-one, 2-cyano-2 - [(4Z) -1 -oxaspiro [5.5] undecan-4-ylidene] methyl acetate (found: m / z 249.1 [MH] +).

Intermediate 9: methyl 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetate

A round bottom flask equipped with a condenser, addition funnel, and rubber septum with nitrogen inlet was charged with a solution of 4-fluoromagnesium bromide (2.0 M in diethyl ether, 7.5 mL, 12.5 mmol ) and CuI (200 mg, 1.0 mmol) in 35 ml of dry diethyl ether. Methyl 2-cyano-2 - [(9Z) -6-oxaspiro [4.5] decan-9-ylidene] acetate (2.5g, 10.5mmol) in diethyl ether (35ml) was added dropwise over 30 min while cooling the reaction flask in an ice bath. The mixture was then stirred at room temperature for 1h. The reaction mixture was poured into a 25 g ice / 1N HCl (20 ml) mixture. The product was extracted with Et ² O (3x50 ml), washed with brine (50 ml), dried (Na2SO4) and concentrated. Purified by ^{normal phase SiO 2} chromatography (8% to 60% EtOAc / hexanes) to provide 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] methyl acetate as a colorless oil (found: 3.24 g, 93%, m / z 331.2 [MH] +).

By the procedure described in the preparation of Intermediate 9 substituting methyl 2-cyano-2 - [(4Z) -2,2-diethyloxane-4-ylidene] acetate for 2-cyano-2 - [(9Z) -6-oxaspiro [4.5] methyl decan-9-ylidene] acetate, methyl 2-cyano-2- [2,2-diethyl-4- (4-fluorophenyl) oxan-4-yl] acetate was prepared (observed: m / z 333.2 [MH] +).

By the procedure described in the preparation of Intermediate 9 substituting 2-cyano-2 - [(4Z) -1-oxaspiro [5.5] undecan-4-ylidene] acetate for methyl 2-cyano-2 - [(9Z) Methyl -6-oxaspiro [4.5] decan-9-ylidene] acetate, 2-cyano-2- [4- (4-fluorophenyl) -1-oxaspiro [5.5] undecan-4-yl] acetate was prepared from methyl (found: m / z 345.2 [MH] +).

Intermediate 10: 2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile

To a previously dissolved solution of KOH (1.1 g, 19.5 mmol) in ethylene glycol (50 ml) was added 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9 methyl -yl] acetate (3.24 g, 9.8 mmol). The mixture was heated to 120 ° C for 3 h, then cooled. H ² O (50 ml) was added, the product was extracted with Et ² Ü (3x50 ml), washed with H ² O (50 ml), dried over Na2SO4, filtered and concentrated (7% to 60% EtOAc / hexanes) to provide methyl 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetate (found: 1.96 g, 73%, m / z 273.2 [MH] +).

1.96 g of the enantiomers were separated by SFC on an AD-3 column using 15% MeOH (0.05% DEA) as a modifier to provide 2 - [(9S) -9- (4-fluorophenyl) -6 -oxaspiro [4.5] decan-9-yl] acetonitrile as a colorless oil (observed: faster eluting enantiomer, 635 mg, 24%, m / z 274.2 [MH] +) and 2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile as a colorless oil (observed: slowest eluting enantiomer, 703 mg, 26%, m / z 273.2 [MH ] +).

By the procedure described in the preparation of Intermediate 10 substituting methyl 2-cyano-2- [2,2-diethyl-4- (4-fluorophenyl) oxan-4-yl] acetate for 2-cyano-2- [9- Methyl (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetate, 2- [2,2-diethyl-4- (4-fluorophenyl) oxan-4-yl] acetonitrile was prepared (observed : mlz 275.2 [MH] +).

By the procedure described in the preparation of Intermediate 10 substituting methyl 2-cyano-2- [4- (4-fluorophenyl) -1-oxaspiro [5.5] undecan-4-yl] acetate for 2-cyano-2- Methyl [9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetate, prepared 2- [4- (4-fluorophenyl) -1-oxaspiro [5.5] undecan-4- yl] acetonitrile (found: m / z 287.2 [MH] +).

Intermediate 11: 2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine

To a solution of 2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile (500 mg, 1.8 mmol) in anhydrous ether (30 ml) at 0 ° C LAH (1.0 M in Et ² O, 3.7 mL, 3.7 mmol) was added dropwise. The reaction was then warmed to room temperature. After 2h the reaction was quenched with 1 ml of H ² O, 0.2 ml of 15% NaOH and then 1 ml of H ² O. The reaction mixture was extracted with Et ² O (3x30 ml), dried over Na ² SO ⁴ and concentrated to provide 2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine as a yellow oil, which was used without further purification (observed: 500 mg, 100%, m / z 277.2 [MH] +).

By the procedure described in the preparation of Intermediate 11 substituting 2- [2,2-diethyl-4- (4-fluorophenyl) oxan-4-yl] acetonitrile for 2 - [(9R) -9- (4-fluorophenyl) - 6-oxaspiro [4.5] decan-9-yl] acetonitrile, 2- [2,2-diethyl-4- (4-fluorophenyl) oxan-4-yl] ethan-1-amine was prepared (observed: m / z , 279.2 [MH] +).

By the procedure described in the preparation of Intermediate 11 substituting 2- [4- (4-fluorophenyl) -1-oxaspiro [5.5] undecan-4-yl] acetonitrile for 2 - [(9R) -9- (4- fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile, 2- [4- (4-fluorophenyl) -1-oxaspiro [5.5] undecan-4-yl] ethan-1-amine ( found: m / z 291.2 [MH] +).

Reference Example 4: Benzyl ({2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl}) amine (Compound 81)

To a solution of amine 2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine (100 mg, 0.361 mmol) in anhydrous ^{CH 2} Cl ² (6 ml) and Na2SO4 (256 mg, 1.80 mmol) at RT was added benzaldehyde (0.055 ml, 0.541 mmol). The reaction stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 6 ml of MeOH at 0 ° C and NaBH4 was added in one portion (16 mg, 0.433 mmol). The reaction was stirred at 0 [deg.] C. for 1 hr. The solution was then quenched with H ² O (20 ml), extracted with CH ² Cl ² (3x30 ml), washed with brine (10 ml) and dried over Na2SO4. The mixture was purified by HPLC to provide benzyl ({2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl}) amine as a white solid (observed: 121 mg, 92%, m / z 368.3 [MH] +).

Intermediate 12: 2,2-diethyloxan-4-ol.

To a mixture of 3-butene-1-ol (19.8 ml, 233 mmol) and 3-pentenone (12.3 ml, 116 mmol) was added 75% sulfuric acid (19.8, 334 mmol; prepared by dilution of 79 mL of conc. sulfuric acid to 100 mL with distilled water) dropwise at 0 ° C. The reaction was allowed to warm to room temperature and was stirred overnight. Water (70 ml) was added to the mixture and then it was neutralized with NaOH (granules) until reaching pH 8 and extracted with diethyl ether (3x150 ml). The ether extract was washed with an aqueous sodium bisulfite solution (40 ml), dried over K ² CO ³ and the ether was evaporated in vacuo. The residue was distilled under reduced pressure to provide 2,2-diethyloxane-4-ol (4.89 g, 27%, B. Pt. 65-7012C at 1mm Hg).

1H NMR (400 MHz, CDCla) 54.04-3.86 (m, 1H), 3.84-3.66 (m, 1H), 3.65-3.38 (m, 1H), 2.06 - 1.95 (m, 1H), 1.92-1.76 (m, 2H), 1.78-1.63 (m, 1H), 1.63-1.50 (m, 1H), 1 , 51-1.31 (m, 3H), 1.28-1.10 (m, 1H), 0.92-0.68 (m, 6H).

Intermediate 13: 2,2-diethyloxane-4-one

To a solution of crude 2,2-diethyloxane-4-ol (500 mg, 3.2 mmol) in CH ² Cl ² (10 ml) were added NMO (750 mg, 6.41 mmol) and 4A molecular sieves ( 2 g). The solution was stirred for 30 min and then TPAP (34 mg, 0.096 mmol) was added in one portion. The reaction was allowed to stir for 10 h. After checking the TLC, the alcohol was gone. It was filtered through a short pad of SiO ² . The filtrate was concentrated and purified by ^{normal phase SiO 2} chromatography (0% to 50% EtOAc / hexanes) to provide 2,2-diethyloxane-4-one (365 mg, 73%).

1H NMR (400 MHz, CDCla) 53.75-3.66 (m, 2H), 3.44-3.29 (m, 2H), 2.51-2.31 (m, 4H), 1.25 -1.4 (m, 4H), 0.75 (m, 6H).

intermediate 14: 2- (bromomagnesium) pyridine

2.0M isopropylmagnesium chloride in THF (6 mL, 12 mmol) was placed in a flask and 2-bromopyridine (1.2 mL, 12 mmol) in ^{anhydrous Et 2} O (4 mL) was added dropwise. The reaction mixture was stirred at RT. for 3h. The resulting mixture was used as is as a 1M Grignard solution.

Reference Example 5: dibenzyl ({2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl}) amine (Compound 225)

To a solution of 2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile (30 mg, 0.13 mmol) in ^{anhydrous CH 2} Cl ² (3 ml ) and Na2SO4 (92.3 mg, 0.65 mmol) at RT, 2.3 eq of benzaldehyde (0.032 ml, 0.32 mmol) were added; the reaction was stirred overnight. NaBH (OAc) 3 (6.6 mg, 0.31 mmol) was added in one portion. The solution was then quenched with H ² O (10 ml), extracted with CH ² Cl ² (3x20 ml), washed with brine (10 ml) and dried over Na2SO4. The solvent was evaporated in vacuo and the residue was purified by HPLC to obtain dibenzyl ({2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl}) amine ( found: 37.4 mg, 50%, m / z 458.3 [MH] +).

Reference Example 6: {2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl} [(3-methylphenyl) methyl] amine (Compound 122)

Following a procedure analogous to that described for Compound 81, Compound 122 was obtained from the corresponding intermediate after chiral HPLC separation (the slowest moving fraction on the AD-3 column). The absolute configuration of Ex. 122 was determined by X-ray crystallography.

Reference Example 7: {2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethyl} [2- (pyridin-3-yl) ethyl] amine (Compound 75)

1.0 M DIBAL solution in toluene (3.0 mL, 3 mmol) was added dropwise to a solution of 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan- 9-yl] acetonitrile (350 mg, 1.4 mmol) in 7 mL of toluene at -78 ° C. The resulting mixture was stirred at -78 ° C until completion (1.5 h). The reaction was then quenched with 5 eq of MeOH (0.28 mL) and 0.1 mL of water, stirred while warming, 175 mg of Na2SO4 were added, stirred at room temperature for 2h to provide 310 mg (80 %) of 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetaldehyde. It was observed: LCMS m / z 250.6 (M 1).

To a solution of 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetaldehyde (50 mg, 0.19 mmol), 5 mL of DCM was added and Na2SO4 (134 mg, 0.95 mmol) 2- (pyridin-3-yl) ethan-1-amine (31 mg, 0.25 mmol) and the reaction was stirred overnight. NaBH4 (9.5 mg, 0.25 mmol) was added, stirred for 10 minutes, 2 drops of MeOH were added, stirred for 1h, quenched with water, the organics were separated and evaporated. The residue was passed through reverse phase Gilson HPLC to provide {2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethyl} [2 - (pyridin-3-yl) ethyl] amine, 65.3 mg (71%). It was observed: 1 Cm S m / z 367.1 (M 1).

Reference Example 8: 2 - [(9R) -9- (2- {4H, 5H, 6H-thieno [2,3-c] pyrrol-5-yl} ethyl) -6-oxaspiro [4.5] decan-9 -yl] pyridine (Compound 82)

To a stirred solution of 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine (0.030 g, 0.115 mmol; prepared following a sequence described for Compound 81 in dry ACN (5.8 mL) 2,3-bis (bromomethyl) thiophene (31.1 mg, 0.115 mmol) was added with subsequent addition of K ² CO ³ (79.62 mg, 0.576 mmol After 30 min, LCMS showed that the reaction was complete and the main peak had the mass corresponding to the desired product. It was then subjected to HPLC purification. HPLC purification method: Luna column of acid medium was used, 10 -50% acetonitrile in H ² O for 15 min, with subsequent flash distillation with 100% acetonitrile, 0.1% TFA modifier. Fractions containing the desired product were pooled, basified with 2N NaOH and extracted with DCM (3x20 mL) The combined organics were concentrated and purified with flash chromatography (10 g silica gel column, elution with 0-10% MeOH in DCM, based on TLC measurements: DCM / MeOH (10/1) Rf = 0.60) to provide 5 mg of 2 - [(9R) -9- (2- {4H, 5H, 6H-thieno [2,3-c ] pyrrol-5-yl} ethyl) -6-oxaspiro [4.5] decan-9-yl] pyridine as a colorless oil in 12% yield. It was observed: LCMS m / z 369 (M 1).

Reference Example 9: {2- [9- (1H-pyrazol-1-yl) -6-oxaspiro [4.5] decan-9-yl] ethyl} (thiophen-2-ylmethyl) amine (Compound 26)

An oven-dried flask equipped with a Dean-Stark apparatus and condenser was cooled to RT under a stream of N ² and charged with 6-oxaspiro [4.5] decan-9-one (0.50 g, 3.24 mmol), (tert-butoxy) carbohydrazide (0.42 g, 3.24 mmol) and hexane (10 mL). The resulting solution was heated to reflux overnight.

It was cooled to RT and the solid was collected by vacuum filtration. The solid was washed with hexane and air dried to provide (tert-butoxy) -N '- [(9Z) -6-oxaspiro [4.5] decan-9-ylidene] carbohydrazide (0.84 g, 96% yield ). It was observed: LCMS m / z 213 (M 1 -t-butyl).

An oven dried flask was charged with (tert-butoxy) -N '- [(9Z) -6-oxaspiro [4.5] decan-9-ylidene] carbohydrazide (0.42 g, 1.56 mmol) and THF. The solution was cooled to 0 ° C and allylmagnesium chloride (2.0 M, 1.60 mL) was added dropwise. The reaction was stirred at 0 ° C for 1 hr and then warmed to RT overnight. LC-MS indicated that the reaction was not complete. Another 2 equivalents of allylmagnesium chloride were added at RT. The solution was stirred for 1h before being quenched with MeOH. The solution was diluted with DCM (60 mL) and H ² O (20 mL). A quantity of precipitates formed and the solid was filtered through a pad of celite. The organic product then it was separated and the aqueous layer was extracted with 10 mL of EtOAc. The combined organic layers were concentrated and the residue was purified on a 25 g Snap column (0-20% tOAc in Hex, 12 CV) to provide (tert-butoxy) -N '- [9- (prop-2-en -1-yl) -6-oxaspiro [4.5] decan-9-yl] carbohydrazide (0.33 g, 68% yield). It was observed: LCMS m / z 333 (M Na).

To a solution of (tert-butoxy) -N '- [9- (prop-2-en-1-yl) -6-oxaspiro [4.5] decan-9-yl] carbohydrazide (0.33 g, 1.06 mmol) in 4 mL of EtOAc was added 4M HCl in dioxane at RT. The solution was stirred at t A until the reaction was complete, which was monitored by LC-MS (30 h). The solvent was then removed and [9- (prop-2-en-1-yl) -6-oxaspiro [4.5] decan-9-yl] hydrazine (250 mg) was obtained. It was observed: LCMS m / z 211.1 (M 1).

To a solution of [9- (prop-2-en-1-yl) -6-oxaspiro [4.5] decan-9-yl] hydrazine (250 mg, 1.0 mmol) in 4 mL of i-PrOH were added Et3N and 3-dimethylaminoacrolein. The solution was refluxed for 3h and then at 50 ° C for 2d. The solvent was removed and the residue was purified on a 25 g Biotage column, eluted with 0-18% EtOAc in Hex (12CV) and 1- [9- (prop-2-en-1-yl) was obtained -6-oxaspiro [4.5] decan-9-yl] -1H-pyrazole (80 mg, 31% yield). It was observed: 1 CMs m / z 247.1 (M 1).

A solution of 1 - [9- (prop-2-en-1 -yl) -6-oxaspiro [4.5] decan-9-yl] -1 H-pyrazole (80 mg, 0.32 mmol) in DCM (5 mL) at -78 ° C was bubbled with O ³ until the solution turned blue. The resulting solution was bubbled with N ² for 5 min. To this was added PPh3 (168 mg, 0.64 mmol) and the solution was stirred for 4h at RT. After removing the solvent, the residue was purified by flash column chromatography to provide 2- [9- (1 H-pyrazol-1-yl) -6-oxaspiro [4.5] decan-9-yl] acetaldehyde (15 mg, 23% yield). It was observed: LCMS m / z 249 (M 1).

A mixture of 2- [9- (1H-pyrazol-1-yl) -6-oxaspiro [4.5] decan-9-yl] acetaldehyde (15 mg, 0.06 mmol) and thiophen-2-ylmethanamine (19 uL, 0.18 mmol) was stirred at RT for 1 hr before adding NaBH (OAc) 3 (25.4 mg, 12 mmol). The solution was stirred overnight. After removing the solvent, the residue was purified by HPLC to provide {2- [9- (1H-pyrazol-1-yl) -6-oxaspiro [4.5] decan-9-yl] ethyl} (thiophen-2-ylmethyl ) amine (17 mg, 61% yield) as a TFA salt. It was observed: LCMS m / z 346 (M 1).

Example 12: Opioid receptor ligands

The opioid receptor ligands and compounds listed in the following tables can be prepared or prepared according to the procedures described above from appropriate starting materials and appropriate reagents. The compounds that have been prepared include NMR data, while the theoretical examples do not include NMR data.

Example 15: Synthesis of [(3-methoxythiophen-2-yl) methyl] ({2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethyl} ) amine (Compound 140).

Methyl 2-Cyano-2- [6-oxaspiro [4.5] decan-9-ylidene] acetate (mixture of E and Z isomers)

A mixture of 6-oxaspiro [4.5] decan-9-one (13.74 g, 89.1 mmol), methylcyanoacetate (9.4 ml, 106.9 mmol), ammonium acetate (1.79 g, 26, 17 mmol) and acetic acid (1.02 ml, 17.8 mmol) in benzene (75 ml) was heated under reflux in a 250 ml round bottom flask equipped with a Dean-Stark and a reflux condenser. After 3h, TLC (25% EtOAc in hexane, PMA spot) showed the reaction to be complete. After cooling, benzene (50 ml) was added and the layer was separated, the organic product was washed with water (120 ml) and the aqueous layer was extracted with CH ² Cl ² (3 x 120 ml). The combined organic product was washed with saturated NaHCO3, brine, dried and concentrated and the residue was purified by flash chromatography (340 g silica gel column, elution by EtOAc in hexane: 5% EtOAc, 2CV; 5- 25%, 14CV; 25-40%, 8 CV) which gave a mixture of E and Z isomers: methyl 2-cyano-2- [6-oxaspiro [4.5] decan-9-ylidene] acetate (it was observed: 18.37 g, 87.8% yield, m / z 236.0 [MH] +) as a clear oil.

Methyl 2-Cyano-2- [9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetate

A solution of 2-bromopyridine (14.4 ml, 150 mm) in THF (75 ml) was added dropwise to a solution of isopropyl magnesium chloride (75 ml, 2M in THF) at 0 ° C in N ² , the mixture Then it was stirred at RT for 3h, copper iodide (2.59 g, 13.6 mmol) was added and it was left to stir at RT for another 30 min before adding a solution of a mixture of E and Z isomers of 2- methyl cyano-2- [6-oxaspiro [4.5] decan-9-ylidene] acetate (16 g, 150 mmol) in THF (60 ml) in 30 min. The mixture was then stirred at RT for 18h. The reaction mixture was poured into a 200 g ice / 2N HCl (100 ml) mixture. The product was extracted with Et ² O (3x300 ml), washed with brine (200 ml), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (100 g silica gel column, elution with EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV which gave 2-cyano-2- [ Methyl 9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetate (found: 15.44 g, 72% yield, m / z 315.0 [MH] +) like an amber oil.

2- [9- (Pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile

Ethylene glycol (300 ml) was added to methyl 2-cyano-2- [9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetate (15.43 g, 49 mmol) and then potassium hydroxide (5.5 g, 98 mmol), the resulting mixture was heated to 120 ° C, after 3 h, the reaction mixture was cooled and water (300 ml) was added, the product was extracted by Et ² O (3 x 400 ml), washed with water (200 ml), dried (Na2SO4) and concentrated, the residue was purified by flash chromatography (340 g silica gel column, elution with EtOAc in hexane : 3% 2CV; 3-25%, 12 CV; 25-40% 6CV to provide 2- [9- (Pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile (observed: 10.37 g, 82% yield, m / z 257.0 [MH] +).

2 - [(9R) -9- (Pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile

-oxaspiro[4.5]decan-9-¡l]aceton¡tr¡lo racémico se separó mediante columna de HPLC quiral en las

-oxaspiro [4.5] decan-9-l] acetonitric racemic was separated by chiral HPLC column in the

following preparative SFC conditions: Instrument: SFC-80 (Thar, Waters); Column: Chiralpak AD-H (Daicel); Column temperature: 402C; Mobile phase: Methanol / CO2 = 40/60; Flow: 70 g / min; Back pressure: 120 Bar; Cycle time of stacked injections: 6.0 min; Injection charge: 225 mg; Under these conditions, 2- [9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile (4.0 g) was separated to provide the desired isomer, 2 - [(9R) -9- (Pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile (2.0 g,> 99.5% enantiomeric excess) as a slow moving fraction. The absolute configuration (R) of the desired isomer was later determined by X-ray crystal structure analysis of Compound 140.

2 - [(9R) -9- (Pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine

LAH (1M in Et ² O, 20ml, 20mmol) was added to a solution of 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile ( 2.56 g, 10 mmol) in Et ² O (100 mL, 0.1M) at 0 ° C under N ² . The resulting mixture was stirred and allowed to warm to room temperature. After 2 h, LCMS showed the reaction to be complete. The reaction was cooled to 0 ° C and quenched with water (1.12 ml), NaOH (10%, 2.24 ml) and another 3.36 ml of water. The solid was filtered and the filter pad was washed with ether (3 x 20 ml). The combined organic product was dried and concentrated to provide 2 - [(9R) -9- (Pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine (observed: 2 , 44 g, 94% yield, m / z 260.6 [MH] +) as a light amber oil.

Alternatively, 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine was prepared by Raney nickel catalyzed hydrogenation.

An autoclave vessel was charged with 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] acetonitrile and ammonia (7N solution in methanol). The resulting solution was stirred under ambient conditions for 15 minutes and treated with Raney 2800 nickel suspended in water. The vessel was pressurized to 0.2 MPa (30 psi) with nitrogen and briefly stirred. The autoclave was vented and the nitrogen purge was repeated two more times. The vessel was pressurized to 0.2 MPa (30 psi) with hydrogen and briefly stirred. The container was vented and purged with hydrogen two more times. The container was pressurized to 0.59-0.62 MPa (85-90 psi) with hydrogen and the mixture warmed to 25-35 ° C. The internal temperature increased to 45-50 ° C for 30-60 minutes. The reaction mixture was stirred at 45-50 ° C for 3 days. The reaction was monitored by HPLC. Once the reaction was judged to be complete, it was cooled to room temperature and filtered through celite. The filter cake was washed with methanol (2x). The combined filtrates were concentrated under reduced pressure at 40-45 ° C. The resulting residue was co-evaporated with EtOH (3x) and dried to obtain a thick syrup of 2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethan-1 -amine.

[(3-Methoxythiophen-2-yl) methyl] ({2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethyl}) amine

2 - [(9R) -9- (Pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethan-1-amine (500 mg, 1.92 mmol), 18 mL of CH ² Cl ² and sodium sulfate (1.3 g, 9.6 mmol). Then 3-methoxythiophene-2-carboxaldehyde (354 mg, 2.4 mmol) was added and the mixture was stirred overnight. NaBH ⁴ (94 mg, 2.4 mmol) was added to the reaction mixture, stirred for 10 minutes and then MeOH (6.0 mL) was added, stirred 1h and finally quenched with water. The organics were separated and evaporated. The crude residue was purified by Gilson's prep HPLC. The desired fractions were collected and concentrated and lyophilized. After lyophilization, the residue was partitioned between CH ² Cl ² and 2N NaOH and the organic layers were collected. After the solvent was concentrated to half volume, 1.0 eq of 1N HCl in Et ² O was added, and most of the solvent was evaporated under reduced pressure. The obtained solid was washed several times with Et ² O and dried to give [(3-methoxythiophen-2-yl) methyl] ({2 - [(9R) -9- (pyridin-2-yl) -6 -oxaspiro [4.5] decan-9-yl] ethyl}) amine (observed: 336 mg, 41% yield, m / z 387.0 [MH] +) as a white solid. The NMR for Compound 140 is described herein.

Reference Example 16: Biological Example

Procedure for the evaluation of antinociception

The hot plate assay is adapted from the procedure originally described by O'Callaghan and Holtzman (JPET, 192, 497, 1975) and is commonly used to determine the potential analgesic efficacy of opioid agonists. The antinociceptive effect of the composition described herein on the hot plate is expressed in% MPE (Maximum Possible Effect).

Rats (175-250g) or mice (20-30g) were acclimatized to the vivarium for at least 48 hrs before the behavioral assessment. Test drugs were administered subcutaneously (SC). The animals were placed on the hot plate, the temperature of which was set at 50-56 ° C, depending on the in vitro potency of the compound. A cut-off time of 30-60 seconds was used, depending on the temperature of the hot plate, so that the paws of the animal that showed analgesia were not damaged by the heat stimulus. The cut-off time was considered a 100% response to thermal stress. Before drug treatment, each animal was evaluated for the baseline response. Thirty minutes after drug administration, the animals were re-evaluated. Dose response experiments were performed to assess the potency of the test compound when multiple doses were administered at the point where maximum analgesia was observed.

The% MPE was calculated according to the following formula:% MPE = [(drug post-latency - baseline latency) / (60 or 30 - baseline latency)] x 100

ED ⁵⁰ values were calculated from the mean% MPE values for each group using log dose response curves by least squares regression analysis.

Table 4

Compound 81: benzyl ({2 - [(9S) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl}) amine

Compound 122: (2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl} [(3-methylphenyl) methyl] amine

Composite 28: benzyl ({2 - [(9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl] ethyl}) amine

Compound 145: {2 - [(9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] decan-9-yl] ethyl} [(5-methylthiophen-2-yl) methyl] amine

Results are shown in Table 4. Naive or control mice typically exhibit hot plate reaction times of 10-15 seconds. The ED50 for morphine in the mouse hot plate was 3.8 mg / kg with full efficacy observed at a dose of 10 mg / kg SC. In comparison, Compound 122 and Compound 28 produced potent efficacy with ED50 of 1.1 and 1.2 mg / kg SC, respectively. These results demonstrate that Compound 122 and Compound 28 produced a stronger analgesic effect in the mouse hot plate assay compared to morphine.

Example 17: In vivo administration to humans (theoretical example)

One or more compounds will be administered in a dosage range of 0.15 mg to 4 mg to a human subject. The compound will be administered as a continuous infusion for more than one hour. The dose can be increased as appropriate to obtain pain relief. The dose increase will usually not exceed 5 times the previous dose. However, dosage amounts can be repeated or decreased as appropriate. The ability of the subjects to withstand or not appreciate pain will be evaluated in comparison with a control group (placebo).

The cold stimulus pain test has been shown to be a reproducible and sensitive measure of the effect of opiates and other centrally acting drugs (Van F and Rolan PE. The utility of the cold pain test to measure analgesia from intravenous morphine. Br. J. Clin. Pharmacol. 1996; 42: 663-664; Posner J. Pain Models in Healthy Volunteers. In: Nimmo WS, Tucker G, eds. Clinical Measurement in Drug Evaluation. 1991, Wolfe Publishing Limited, UK .; Wotherspoon HA, Kenny GNC, McArdle CS. Analgesic Efficacy of Controlled-Release DihydroCodeine. Anaesthesia 1991; 46: 915-917 .; Lamb RJ, Mercer AJ, Posner J. The effect of lamotrigine (300 mg) and dipipanone (4 mg and 8 mg), alone and in combination, on the cold-pain test in healthy volunteers. Br. J. Clin. Pharmacol. 1994; 39: 539-588P.). In the test, a subject's hand is immersed in water that has cooled to a range of 1 to 3 ° C. The initial feeling of cold is replaced by a deep burning discomfort in the hand that is mediated by nociceptors in the veins. The discomfort gradually builds to a plateau over about 90 seconds and then persists or subsides slightly. The stimulus is easily controlled and the response is reproducible. The technique has been shown to be sensitive for different doses of analgesic drugs.

During the cold stimulus pain test, the subject will sit down and place their non-dominant hand in a thermostatically controlled water bath, shaken at approximately 2 ° C. With the other hand the subject can adjust a visual analog scale on a computer screen using the arrow keys on the keyboard. The scale is labeled "no pain" at one end and "maximum pain" at the other end. The pointer will initially be at the "painless" end and the subject will move the pointer along the line to rate their feelings continuously throughout the testing period. At the end of the 2 minutes the computer will automatically instruct the subject to remove their hand which can then be dried. The cold stimulus pain test has been used extensively in healthy volunteer studies and is noninvasive.

It is expected that the administration of the compound will allow the human subject to feel no pain or feel less pain compared to the control group.

Although the compounds described herein have been described with reference to examples, those skilled in the art will recognize that various modifications can be made without departing from the scope that is defined by the appended claims.

Claims (14)

1. A pharmaceutical composition comprising a compound having a formula of

or a pharmaceutically acceptable salt thereof, for use in the treatment of pain by parenteral administration. 2. The pharmaceutical composition for use according to claim 1, wherein the compound has a formula of

or a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition for use according to claims 1 or 2, wherein the parenteral administration is intravenous, intraperitoneal, intravesical or intrathecal. 4. The pharmaceutical composition for use according to any of the preceding claims, wherein the pain is postoperative pain, neuropathic pain, inflammation pain or trauma pain. 5. The pharmaceutical composition for use according to any one of claims 1-4, wherein the pharmaceutical composition comprises 0.15 mg to 4 mg of the compound or a pharmaceutically acceptable salt thereof. 6. The pharmaceutical composition for use according to any one of claims 1-4, wherein the pharmaceutical composition comprises about 0.01 mg to about 250 mg of the compound, or a pharmaceutically acceptable salt thereof. 7. The pharmaceutical composition for use according to claim 6, wherein the pharmaceutical composition comprises 0.1 mg to 200 mg of the compound, or a pharmaceutically acceptable salt thereof. 8. The pharmaceutical composition for use according to any one of claims 1-7, wherein a hydrogen of the compound is substituted in any position with a deuterium. 9. A pharmaceutical composition comprising 0.01 mg to 250 mg of a compound of formula

or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises 0.1 mg to 200 mg of the compound or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claims 9 or 10, wherein the pharmaceutical composition comprises 0.15 mg to 4 mg of the compound, or a pharmaceutically acceptable salt thereof. 12. The pharmaceutical composition of any one of claims 9-11, wherein the pharmaceutical composition is for parenteral or intravenous administration. 13. The pharmaceutical composition of any one of claims 9-12, wherein the compound has a formula of

or a pharmaceutically acceptable salt thereof. 14. The pharmaceutical composition of any one of claims 9-13, wherein a hydrogen of the compound is substituted in any position with a deuterium.